A naturally occurring variant of<i>MBD4</i>causes maternal germline hypermutation in primates

Stendahl, Alexandra M.; Sanghvi, Rashesh; Peterson, Samuel; Ray, Karina; Lima, Ana C.; Rahbari, Raheleh; Conrad, Donald F.

doi:10.1101/gr.277977.123

Cited by 4 publications

References 36 publications

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A maternal germline mutator phenotype in a family affected by heritable colorectal cancer

Young,

Beichman,

Mas-Ponte

et al. 2023

Preprint

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Variation in DNA repair genes can increase cancer risk by elevating the rate of oncogenic mutation. Defects in one such gene,MUTYH, are known to elevate the incidence of colorectal cancer in a recessive Mendelian manner, and some evidence has also linkedMUTYHto elevated incidence of other cancers as well as elevated mutation rates in normal somatic and germline cells. Here, we use whole genome sequencing to measure germline de novo mutation rates in a large extended family affected by pathogenicMUTYHvariation and a history of colorectal cancer. Although this family’s genotype, p.Y179C/V234M (c.536A>G/700G>A on transcript NM_001128425), contains a variant with conflicting functional interpretations, we use anin vitrocell line assay to determine that it partially attenuates MUTYH’s function. In the children of mothers affected by the Y179C/V234M genotype, we identify an elevation of the C>A mutation rate that is weaker than mutator effects previously reported to be caused by other pathogenicMUTYHgenotypes, suggesting that mutation rates in normal tissues may be useful for classifying cancer-associated variation along a continuum of severity. Surprisingly, we detect no significant elevation of the C>A mutation rate in children born to a father with the same biallelicMUTYHgenotype, despite calculating that we should have adequate power to detect such a mutator effect. This suggests that the oxidative stress repaired byMUTYHmay contribute more to female reproductive aging than male reproductive aging in the general population.

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A maternal germline mutator phenotype in a family affected by heritable colorectal cancer

Young,

Beichman,

Mas-Ponte

et al. 2023

Preprint

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The Evolutionary Interplay of Somatic and Germline Mutation Rates

Beichman,

Zhu,

Harris

2024

Annual Review of Biomedical Data Science

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Novel sequencing technologies are making it increasingly possible to measure the mutation rates of somatic cell lineages. Accurate germline mutation rate measurement technologies have also been available for a decade, making it possible to assess how this fundamental evolutionary parameter varies across the tree of life. Here, we review some classical theories about germline and somatic mutation rate evolution that were formulated using principles of population genetics and the biology of aging and cancer. We find that somatic mutation rate measurements, while still limited in phylogenetic diversity, seem consistent with the theory that selection to preserve the soma is proportional to life span. However, germline and somatic theories make conflicting predictions regarding which species should have the most accurate DNA repair. Resolving this conflict will require carefully measuring how mutation rates scale with time and cell division and achieving a better understanding of mutation rate pleiotropy among cell types.

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Epistasis between mutator alleles contributes to germline mutation spectrum variability in laboratory mice

Sasani

Quinlan

Harris

2024

eLife

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Maintaining germline genome integrity is essential and enormously complex. Hundreds of proteins are involved in DNA replication and proofreading, and hundreds more are mobilized to repair DNA damage [1]. While loss-of-function mutations in any of the genes encoding these proteins might lead to elevated mutation rates, mutator alleles have largely eluded detection in mammals. DNA replication and repair proteins often recognize particular sequence motifs or excise lesions at specific nucleotides. Thus, we might expect that the spectrum of de novo mutations — that is, the frequency of each individual mutation type (C>T, A>G, etc.) — will differ between genomes that harbor either a mutator or wild-type allele at a given locus. Previously, we used quantitative trait locus mapping to discover candidate mutator alleles in the DNA repair gene Mutyh that increased the C>A germline mutation rate in a family of inbred mice known as the BXDs [2, 3]. In this study we developed a new method, called “inter-haplotype distance,” to detect alleles associated with mutation spectrum variation. By applying this approach to mutation data from the BXDs, we confirmed the presence of the germline mutator locus near Mutyh and discovered an additional C>A mutator locus on chromosome 6 that overlaps Ogg1 and Mbd4, two DNA glycosylases involved in base-excision repair [4, 5]. The effect of a chromosome 6 mutator allele depended on the presence of a mutator allele near Mutyh, and BXDs with mutator alleles at both loci had even greater numbers of C>A mutations than those with mutator alleles at either locus alone. Our new methods for analyzing mutation spectra reveal evidence of epistasis between germline mutator alleles, and may be applicable to mutation data from humans and other model organisms.

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A naturally occurring variant ofMBD4causes maternal germline hypermutation in primates

Cited by 4 publications

References 36 publications

A maternal germline mutator phenotype in a family affected by heritable colorectal cancer

A maternal germline mutator phenotype in a family affected by heritable colorectal cancer

The Evolutionary Interplay of Somatic and Germline Mutation Rates

Epistasis between mutator alleles contributes to germline mutation spectrum variability in laboratory mice

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